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(Circulation. 2004;110:e27-e31.)
© 2004 American Heart Association, Inc.

Clinician Update

Cardiopulmonary Exercise Testing

How Do We Differentiate the Cause of Dyspnea?

Richard V. Milani, MD; Carl J. Lavie, MD; Mandeep R. Mehra, MD

From the Department of Cardiology, Ochsner Clinic Foundation, New Orleans, La.

Correspondence to Richard V. Milani, MD, Ochsner Heart and Vascular Institute, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70121. E-mail rmilani{at}ochsner.org

	Introduction

Top Introduction Background Metabolic Derangements in... Pitfalls in CPX Interpretation Conclusions References

 
Case report: A 54-year-old man is referred for dyspnea on exertion. He has a history of type II diabetes and 35 pack-years of smoking. He suffered an anterior myocardial infarction 14 months ago, and on recent echocardiography was found to have an ejection fraction of 25%. Since his myocardial infarction, he has quit smoking and has gained an additional 27 pounds. He admits to a sedentary lifestyle and has recently tried to initiate an exercise program in an effort to lose weight. His current body mass index is 33.4 kg/m². He denies orthopnea but does have progressive lower-extremity edema.

What is the primary cause of his dyspnea? Is it ventilatory or circulatory? Obesity or deconditioning? What is the prognosis for his ischemic cardiomyopathy? What would be the appropriate diagnostic study to obtain these answers?

	Background

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Exercise stress testing is commonly used in clinical practice to evaluate the presence and severity of coronary ischemia. A significant enhancement of clinical information available during exercise can be obtained by concurrent measurement of respiratory gas exchange via use of a metabolic cart. This modality of stress testing has been called cardiopulmonary stress testing (CPX). This article will update the cardiovascular clinician on the utility of CPX in the modern cardiovascular practice.

A major function of the cardiovascular system is gas exchange, supplying O₂ and other fuels to working muscles, as well as removal of CO₂ and other metabolites. The heart, lungs, and pulmonary and systemic circulations form a single circuit for exchange of respiratory gases between the environment and the cells of the body.^1,2 Under steady-state conditions, respiratory oxygen uptake (O₂) and carbon dioxide outflow (CO₂) measured at the mouth are equivalent to oxygen utilization (O₂) and carbon dioxide production (CO₂) occurring in the cell, thus "external respiration" equals "internal respiration." CPX directly measures O₂, CO₂, and air flow (minute ventilation [E], tidal volume, and respiratory rate) on a breath-by-breath basis using a nonrebreathing valve connected to a metabolic cart. Samples of expired air are typically assessed every 15 seconds, and real-time data are expressed in both a tabular and graphic format. Additionally, oxygen saturation using finger or ear oximetry is monitored and recorded. From these data, numerous clinically relevant metabolic parameters can be derived (Table 1). The abbreviations used subsequently are explained in Table 1.

View this table: [in this window] [in a new window]   TABLE 1. Metabolic Parameters Measured or Derived From CPX

	Metabolic Derangements in Disease

Top Introduction Background Metabolic Derangements in... Pitfalls in CPX Interpretation Conclusions References

 
Metabolic derangements can occur at multiple sites within the circuitry of gas exchange, including the consumers at the muscle mitochondria, the transporters within the circulatory system, to the exchangers at the site of ventilation (Figure 1). Knowledge of site and extent of metabolic dysfunction can have a wide application in clinical medicine (Table 2).

View larger version (34K): [in this window] [in a new window]   Figure 1. Derangements of gas exchange in disease. The gears represent the functional interdependence of the physiological components of the system. Reproduced with permission from Wasserman et al.2

View this table: [in this window] [in a new window]   TABLE 2. Indications for CPX

CPX provides an ideal modality for the evaluation of patients presenting with exertional dyspnea and fatigue, at which time the clinician is faced with a breadth of differential diagnoses ranging from circulatory impairment to deconditioning. Standard diagnostic studies may not identify the true cause because circulatory and ventilatory reserves cannot be assessed from indices of resting cardiac and pulmonary function.³ By virtue of obtaining gas exchange data under the provocation of exercise, CPX can discriminate among many subtle and often overlapping etiologies.

Etiology of Dyspnea
Using the algorithm provided in Figure 2, a peak oxygen uptake (PkO₂) <85% of that predicted by age and gender is considered to be low, and a normal anaerobic threshold (AT) is generally closer to 60% of the predicted PkO₂. For purposes of classification, an AT <40% of the predicted peak O₂ is considered pathologically reduced and indicative of circulatory insufficiency. A breathing reserve (BR) <30% would indicate ventilatory impairment, especially when accompanied by oxygen desaturation with exercise, although a BR of 20% to 30% is deemed a borderline value. CPX is very useful in dyspneic patients with combined cardiac and pulmonary diseases who may have a reduction in both AT and BR, the more dominant of which may indicate the primary cause of the patient’s functional limitation. A respiratory exchange ratio (RER) of <1.1 (particularly <1.0) in the absence of other metabolic abnormalities suggests poor effort, anxiety, or mild disease. Finally, this type of evaluation can be helpful in patients being evaluated for employment disability.

View larger version (31K): [in this window] [in a new window]   Figure 2. Flow chart for the differential diagnosis of exertional dyspnea and fatigue. Used with permission from Wasserman et al.2

Heart Failure Prognosis
From a clinical standpoint, probably the greatest utilization of CPX has been in the evaluation of patients with advanced systolic heart failure, in which CPX has gained widespread use by virtue of its superior prognostic capabilities in these patients. In the Veterans Administration Heart Failure Trial (V-HeFT), the mortality rate of patients with a O₂max 14.5 mL/kg per minute was double that of patients whose O₂max exceeded this value, a finding more significant than the drug treatment effect being studied.⁴ In a separate investigation of heart failure patients referred for cardiac transplantation, Mancini et al⁵ found that PkO₂ was the single best predictor of survival. Moreover, transplantation could be safely deferred in patients whose PkO₂ was >14 mL/kg per minute, where their survival exceeded that of patients undergoing heart transplantation. As a result of these seminal studies, CPX remains a pivotal modality in initial evaluation of patients with advanced heart failure, especially those who are considered for heart transplantation. The commonly used Weber-Janicki classification of exercise capacity in heart failure is provided in Table 3.⁶

View this table: [in this window] [in a new window]   TABLE 3. Functional Impairment During Incremental Treadmill Testing in Heart Failure: Weber-Janicki Classification*

Although a PkO₂ cutoff of 14 mL/kg per minute remains an important prognostic discriminator in heart failure patients, our laboratory and others have described disparities in its prognostic utility when evaluating patients with intermediate levels of PkO₂ (between 10 and 18 mL/kg per minute) as well as in special populations such as women and obese patients.^7–9 Investigators have therefore sought to evaluate the predictive strength of other metabolic parameters in advanced heart failure, including percent predicted PkO₂,¹⁰ ventilation/carbon dioxide production ratio and slope,¹¹ oxygen consumption recovery,¹² and O₂ pulse.^13,14 Each investigation demonstrated variability with regard to each parameter’s predictive strength. Moreover, a recent investigation suggests that the widespread use of ß-blocker therapy in heart failure may require alteration of the PkO₂ cutoff point of 14 mL/kg per minute to a lower value.¹⁵

A fundamental understanding of O₂ consumption may explain the disparate observations in women and obese patients. Although PkO₂ is corrected for total body weight, body fat is "metabolically inert," consuming essentially no oxygen, and can represent a significant portion of total weight. Moreover, considerable variability in body composition is present across populations, including those with heart failure. We demonstrated that correcting PkO₂ for lean body mass (PkO₂lean) provides a more refined discriminator of outcome than traditionally reported total weight–adjusted values.¹⁶ In heart failure patients, a PkO₂lean cutoff of 19 mL/kg per minute provides a more robust discriminator than the total weight–adjusted figure of 14 mL/kg per minute. As such, we routinely assess body fat using the 3-site skinfold method before each CPX study to calculate lean body mass.¹⁷ From a practical standpoint, this adds only 3 to 4 minutes to the time required to perform a CPX. Using the lean adjusted peak oxygen uptake, we eliminated previously observed disparities between genders, and between obese and nonobese patients, in predicting outcome in heart failure. We also reported the usefulness of peak O₂ pulse (cutoff value 10 mL/beat), especially when corrected for lean body mass (cutoff value 14 mL/beat), in predicting prognosis in patients with chronic systolic heart failure.¹⁸

Less commonly, clinicians need to evaluate heart failure patients who have very limited exercise tolerance resulting from low threshold angina or severe ventricular arrhythmias, in which an early exercise surrogate of PkO₂ would be required for risk stratification. Our laboratory and others successfully used the pattern of E/CO₂ change during early exercise to predict PkO₂ and subsequent outcome in such patients.^11,19,20 We found that a decrease in E/CO₂ of <10% early in exercise predicts a PkO₂ of <14 mL/kg per minute and poor outcome in patients with heart failure.

	Pitfalls in CPX Interpretation

Top Introduction Background Metabolic Derangements in... Pitfalls in CPX Interpretation Conclusions References

 
In general, data obtained from CPX are reliable and reproducible, but as with any clinical modality, there may be pitfalls in collecting and interpreting metabolic data obtained during exercise. Among the most important requirements in performing CPX is a skilled technician who provides thorough instruction to patients before testing, as well as encouragement during exercise. The technician must be meticulous in monitoring data as they are acquired and be cognizant of system leaks (breathing around mouthpiece, nasal breathing, or sampling line leaks) in data acquisition.

O₂ is now a commonly used end point in various clinical investigations, particularly heart failure trials.^21–23 Changes in PkO₂, therefore, may have important prognostic and therapeutic consequences.^24,25 An increase in PkO₂ by as little as 1 mL/kg per minute can mean as much as a 69-second gain in treadmill exercise time, as well as improved cardiovascular outcomes.^24,26 In this context, however, it is important to remember that several factors, including effort, can influence the PkO₂ value. Consequently, PkO₂ may not always be the appropriate metabolic end point to evaluate the effects of a given intervention (Figure 3). Because PkO₂ can be effort dependent, Pina and Karalis²⁷ demonstrated that AT rather than PkO₂ was a more reproducible and effort-independent parameter in heart failure patients undergoing serial testing. Therefore, AT and knowledge of RER must accompany PkO₂ data when making clinical decisions, particularly with regard to results of therapeutic interventions.²⁸ In the less common event that AT is not achieved, an occurrence in up to 30% of our heart failure population, we successfully used the pattern of E/CO₂ change in early exercise to predict PkO₂ and subsequent outcomes in such patients.^11,19,20

View larger version (15K): [in this window] [in a new window]   Figure 3. Metabolic endpoint to evaluate results of therapeutic interventions. (See Table 1 for abbreviations.) *, particularly useful in women and obese patients.

	Conclusions

Top Introduction Background Metabolic Derangements in... Pitfalls in CPX Interpretation Conclusions References

 
Returning to our case study, the patient exercised for 9 minutes on an intermediate ramping protocol, stopping secondary to shortness of breath, achieving a peak heart rate of 149 bpm (90% of predicted). There were no electrocardiographic changes suggestive of ischemia. The principal metabolic data were as follows:

PkO₂=19.2 mL/kg per minute (63% of predicted), measured metabolic equivalents =5.5

PkO₂lean=30.33 mL/kg per minute (% body fat =36.7%)

AT=15.5 mL/kg per minute (51% of predicted)

BR=32%

Oxygen saturation at peak=98%

RER=1.13

On the basis of the interpretative schema in Figure 2, we conclude that this patient demonstrated an adequate effort (RER 1.1) with a low peak aerobic capacity (PkO₂ 63% of predicted). The AT was normal, suggesting adequate circulatory status. Additionally, the BR and O₂ saturation at peak exercise were in the normal range, thereby excluding a ventilatory etiology to the patient’s symptoms. Despite the underlying presence of a cardiomyopathy, the most likely explanation for the patient’s symptoms is deconditioning, in large part due to the patient’s obesity. The cardiopulmonary data suggest a very favorable prognosis for his cardiomyopathy. The patient’s symptoms can be improved and possibly eliminated by enrollment into a structured conditioning program of exercise training.

	References

Top Introduction Background Metabolic Derangements in... Pitfalls in CPX Interpretation Conclusions References

 

1. Weber KT, Janicki JS, Shroff SG, Likoff MJ. The cardiopulmonary unit: the body’s gas transport system. Clin Chest Med. 1983; 4: 101–110.[Medline] [Order article via Infotrieve]
   
2. Wasserman K, Hansen J, Sue D, Casaburi R, Whipp B. Principles of Exercise Testing and Interpretation. Philadelphia, Pa: Lea & Febiger; 1999.
   
3. Neuberg GW, Friedman SH, Weiss MB, Herman MV. Cardiopulmonary exercise testing: the clinical value of gas exchange data. Arch Intern Med. 1988; 148: 2221–2226.[Abstract]
   
4. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkman WB, Loeb H, Wong M, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991; 325: 303–310.[Abstract]
   
5. Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH Jr, Wilson JR. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation. 1991; 83: 778–786.[Abstract/Free Full Text]
   
6. Weber KT, Kinasewitz GT, Janicki JS, Fishman AP. Oxygen utilization and ventilation during exercise in patients with chronic cardiac failure. Circulation. 1982; 65: 1213–1223.[Abstract/Free Full Text]
   
7. Richards DR, Mehra MR, Ventura HO, Lavie CJ, Smart FW, Stapleton DD, Milani RV. Usefulness of peak oxygen consumption in predicting outcome of heart failure in women versus men. Am J Cardiol. 1997; 80: 1236–1238.[CrossRef][Medline] [Order article via Infotrieve]
   
8. Lavie CJ, Milani R, Mehra MR, Ventura HO, Messerli FH. Obesity, weight reduction and survival in heart failure. J Am Coll Cardiol. 2002; 39: 1563; author reply 2002;39:1563–1564.[Free Full Text]
   
9. Lavie CJ, Osman AF, Milani RV, Mehra MR. Body composition and prognosis in chronic systolic heart failure: the obesity paradox. Am J Cardiol. 2003; 91: 891–894.[CrossRef][Medline] [Order article via Infotrieve]
   
10. Stelken AM, Younis LT, Jennison SH, Miller DD, Miller LW, Shaw LJ, Kargl D, Chaitman BR. Prognostic value of cardiopulmonary exercise testing using percent achieved of predicted peak oxygen uptake for patients with ischemic and dilated cardiomyopathy. J Am Coll Cardiol. 1996; 27: 345–352.[Abstract]
    
11. Milani RV, Mehra MR, Reddy TK, Lavie CJ, Ventura HO. Ventilation/carbon dioxide production ratio in early exercise predicts poor functional capacity in congestive heart failure. Heart. 1996; 76: 393–396.[Abstract/Free Full Text]
    
12. Robbins M, Francis G, Pashkow FJ, Snader CE, Hoercher K, Young JB, Lauer MS. Ventilatory and heart rate responses to exercise: better predictors of heart failure mortality than peak oxygen consumption. Circulation. 1999; 100: 2411–2417.[Abstract/Free Full Text]
    
13. Cohen-Solal A, Barnier P, Pessione F, Seknadji P, Logeart D, Laperche T, Gourgon R. Comparison of the long-term prognostic value of peak exercise oxygen pulse and peak oxygen uptake in patients with chronic heart failure. Heart. 1997; 78: 572–576.[Abstract/Free Full Text]
    
14. Cohen-Solal A, Tabet JY, Logeart D, Bourgoin P, Tokmakova M, Dahan M. A non-invasively determined surrogate of cardiac power (‘circulatory power’) at peak exercise is a powerful prognostic factor in chronic heart failure. Eur Heart J. 2002; 23: 806–814.[Abstract/Free Full Text]
    
15. Zugck C, Haunstetter A, Kruger C, Kell R, Schellberg D, Kubler W, Haass M. Impact of beta-blocker treatment on the prognostic value of currently used risk predictors in congestive heart failure. J Am Coll Cardiol. 2002; 39: 1615–1622.[Abstract/Free Full Text]
    
16. Osman AF, Mehra MR, Lavie CJ, Nunez E, Milani RV. The incremental prognostic importance of body fat adjusted peak oxygen consumption in chronic heart failure. J Am Coll Cardiol. 2000; 36: 2126–2131.[Abstract/Free Full Text]
    
17. Jackson AS, Pollock ML. Practical assessment of body composition. Physician Sports Med. 1985; 13: 76–90.
    
18. Lavie CJ, Milani RV, Mehra MR. Peak exercise oxygen pulse and prognosis in chronic heart failure. Am J Cardiol. 2004; 93: 588–593.[CrossRef][Medline] [Order article via Infotrieve]
    
19. Kleber FX, Vietzke G, Wernecke KD, Bauer U, Opitz C, Wensel R, Sperfeld A, Glaser S. Impairment of ventilatory efficiency in heart failure: prognostic impact. Circulation. 2000; 101: 2803–2809.[Abstract/Free Full Text]
    
20. Koike A, Itoh H, Kato M, Sawada H, Aizawa T, Fu LT, Watanabe H. Prognostic power of ventilatory responses during submaximal exercise in patients with chronic heart disease. Chest. 2002; 121: 1581–1588.[Abstract/Free Full Text]
    
21. Mancini DM, Katz SD, Lang CC, LaManca J, Hudaihed A, Androne AS. Effect of erythropoietin on exercise capacity in patients with moderate to severe chronic heart failure. Circulation. 2003; 107: 294–299.[Abstract/Free Full Text]
    
22. Giannuzzi P, Temporelli PL, Corra U, Tavazzi L. Antiremodeling effect of long-term exercise training in patients with stable chronic heart failure: results of the Exercise in Left Ventricular Dysfunction and Chronic Heart Failure (ELVD-CHF) trial. Circulation. 2003; 108: 554–559.[Abstract/Free Full Text]
    
23. Jaski BE, Lingle RJ, Kim J, Branch KR, Goldsmith R, Johnson MR, Lahpor JR, Icenogle TB, Pina I, Adamson R, Favrot LK, Dembitsky WP. Comparison of functional capacity in patients with end-stage heart failure following implantation of a left ventricular assist device versus heart transplantation: results of the experience with left ventricular assist device with exercise trial. J Heart Lung Transplant. 1999; 18: 1031–1040.[CrossRef][Medline] [Order article via Infotrieve]
    
24. Grigioni F, Barbieri A, Magnani G, Potena L, Coccolo F, Boriani G, Specchia S, Carigi S, Musuraca A, Zannoli R, Magelli C, Branzi A. Serial versus isolated assessment of clinical and instrumental parameters in heart failure: prognostic and therapeutic implications. Am Heart J. 2003; 146: 298–303.[CrossRef][Medline] [Order article via Infotrieve]
    
25. Ventura HO, Mehra MR. Hippocrates and prognosis in heart failure: the challenge of static and dynamic measurements. Am Heart J. 2003; 146: 215–217.[CrossRef][Medline] [Order article via Infotrieve]
    
26. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, Ellestad M, Trupp RJ, Underwood J, Pickering F, Truex C, McAtee P, Messenger J. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002; 346: 1845–1853.[Abstract/Free Full Text]
    
27. Pina IL, Karalis DG. Comparison of four exercise protocols using anaerobic threshold measurement of functional capacity in congestive heart failure. Am J Cardiol. 1990; 65: 1269–1271.[CrossRef][Medline] [Order article via Infotrieve]
    
28. Mezzani A, Corra U, Bosimini E, Giordano A, Giannuzzi P. Contribution of peak respiratory exchange ratio to peak VO2 prognostic reliability in patients with chronic heart failure and severely reduced exercise capacity. Am Heart J. 2003; 145: 1102–1107.[CrossRef][Medline] [Order article via Infotrieve]
    

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This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Milani, R. V. Articles by Mehra, M. R. Search for Related Content PubMed PubMed Citation Articles by Milani, R. V. Articles by Mehra, M. R. Pubmed/NCBI databases Medline Plus Health Information Breathing Problems Related Collections Congestive Exercise testing Exercise/exercise testing/rehabilitation